© 2000 American Heart Association, Inc.
Integrative Physiology |
ß-Blockade Prevents Sustained Metalloproteinase Activation and Diastolic Stiffening Induced by Angiotensin II Combined With Evolving Cardiac Dysfunction
From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions (H.S., N.P., D.A.K.), and the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging (Y.A.G., M.T.C.), Baltimore, Md; the Section of Cardiovascular Science, DeBakey Heart Center, Department of Medicine, Methodist Hospital and Baylor College of Medicine, Houston, Tex (M.L.L.); and the Department of Anatomy, Physiology, and Pharmacology, Auburn University, Auburn, Ala (J.S.J.).
Correspondence to David A. Kass, MD, Halsted 500, Division of Cardiology, Johns Hopkins Medical Institutions, 600 N Wolfe St, Baltimore, MD 21287. E-mail dkass{at}bme.jhu.edu
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Abstract |
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Abstract—Angiotensin II (Ang II)–mediated sympathostimulation may worsen the progression of cardiac failure, although the nature and mechanisms of such interactions are largely unknown. We previously demonstrated that Ang II combined with evolving cardiodepression (48-hour tachycardia pacing, 48hP) induces marked chamber stiffening and increases metalloproteinases (MMPs). Here, we test the hypothesis that both abnormalities stem from sympathostimulatory effects of Ang II. Forty-eight dogs were instrumented to serially assess conscious ventricular mechanics, MMP abundance and activity, and myocardial histopathology. 48hP combined with 5 days of Ang II (15±5 ng · kg-1 · min-1 IV) more than doubled chamber stiffness (end-diastolic pressure >25 mm Hg, P<0.001), whereas stiffness was unchanged by Ang II or 48hP alone. In vitro and in situ zymography revealed increased MMP abundance and activity (principally 92-kDa gelatinase) from Ang II+48hP. Both stiffening and MMP changes were prevented by cotreatment with high-dose atenolol (which nearly fully inhibited isoproterenol-induced inotropy) but not partial ß-blockade. Myocellular damage with fibroblast/neutrophil infiltration from Ang II+48hP was also inhibited by high- but not low-dose atenolol, whereas collagen content was not elevated with either dose. These data support a role of sympathostimulation by Ang II in modulating myocardial MMP abundance and activity and diastolic stiffening in evolving heart failure and suggest a novel mechanism by which ß-blockade may limit chamber remodeling and diastolic dysfunction.
Key Words: angiotensin II • heart failure • metalloproteinase • diastole • ß-receptor blocker
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Introduction |
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Dilated cardiomyopathy remains a leading cause of morbidity and mortality, resulting in nearly 1 million hospitalizations per year in the United States alone.1 The disease is initiated by a myocardial insult resulting in a sustained incapacity to deliver adequate cardiac output and systolic pressure. However, it is the complex interplay of primary dysfunction with reactive neurohumoral stimulation and molecular signaling that ultimately worsens function and leads to progressive remodeling and the induction of counterproductive molecular responses.2 3 An appreciation for such interactions has refocused therapeutic efforts over the past decade from agents targeting hemodynamics to those inhibiting neurohormones.2 3 4 5 6
Among the leading factors thought to adversely influence the failing heart is angiotensin II (Ang II), with plasma and myocardial levels often rising later in the evolution of dilated cardiomyopathy.7 Ang II has both direct and sympathostimulatory effects on the myocardium. Direct effects in normal tissue include positive inotropic and hypertrophic signaling,8 9 10 11 whereas in failing hearts, the response reportedly switches to negative inotropy and lusitropy.12 Sympathostimulatory effects stem from presynaptic and postsynaptic modulation of norepinephrine (NE) and baroreflex modulation.13 14 15 16 This pathway may also be important, because previous studies have shown that Ang II–mediated myocardial tissue damage in rats is inhibited by propranolol.17 18
Ang II also influences the extracellular matrix by altering collagen19 20 21 and the abundance and activity of metalloproteinases (MMPs).19 20 21 22 Increased MMPs are reported in late-state experimental and human heart failure23 24 25 and may play a role in chamber remodeling and diastolic decompensation. In this regard, we recently reported that combining exogenously administered Ang II with evolving cardiodepression induced by 48 hours of tachycardia pacing (Ang II+48hP) stimulated MMPs and also markedly exacerbated diastolic stiffening.22 Whether this synergistic interaction and MMP change were a result of direct Ang II–mediated effects or of toxicity related to sympathostimulation remains unknown. Accordingly, the present study tested the hypothesis that ß-blockade can offset both diastolic stiffening and increased MMP abundance and tissue activity from Ang II+48hP. The results reveal substantial interplay between Ang II, ß-adrenergic activation, cardiodepression, and MMP activity and support a major role of adrenergic signaling in Ang II–mediated diastolic dysfunction with evolving heart failure. They further support a novel mechanism by which ß-blockade may ameliorate chamber remodeling and improve diastolic function in heart failure26 by countering Ang II–modulated sympathostimulation.
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Materials and Methods |
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Animal Preparation
Forty-eight adult mongrel dogs of either sex (45 to 65 lb) were studied. The protocol and procedures were approved by the Animal Care and Use Committee of the Johns Hopkins Medical Institutions. Dogs were chronically instrumented to measure right atrial and left ventricular cavity pressure and left ventricular anteroposterior dimension and to perform transient inferior vena cava occlusion to assess left ventricular pressure-dimension relations. Rapid right ventricular pacing was achieved with a programmable stimulator (Spectrax, Medtronics). Exogenous intravenous Ang II was provided by osmotic pump (Alzet 2 ML1). Details of the preparation have been reported.22
Protocol
Five animal groups were studied. Group 1 animals (n=13) were
exposed to 6 to 7 days of Ang II infusion (15.3±4.5 ng ·
kg-1 · min-1 in
0.01N acetic acid), with right ventricular tachypacing (240
bpm) superimposed during the final 48 hours. The Ang II dose yields
plasma levels of 150 to 200 pg/mL,22 similar to human and
experimental heart failure.27 Group 2 animals received 1
week of oral atenolol before and during the Ang II+48hP protocol at 2
doses: 0.18±0.01 g/d atenolol (low-dose group 2A, n=8) and 2.8±0.5
g/d (high-dose group 2B, n=9). Additional control groups included dogs
undergoing 48-hour tachycardia pacing (48hP) only (group 3,
n=12) and those exposed only to 7 days of Ang II (group 4, n=6). Data
from groups 1, 3, and 4 have been reported previously.22
Hemodynamics were recorded in conscious animals,
with pacing suspended at least 30 minutes before study. Left
ventricular endomyocardial biopsies
were obtained serially for tissue analysis.22
Hemodynamic Analysis
Hemodynamic data were digitized at 250 Hz, and
both steady-state and pressure-dimension parameters were
derived.22 Fractional shortening, maximal rate of pressure
rise (dP/dtmax), slope of stroke work
(pressure-dimension loop area)-end-diastolic dimension
(EDD) relation, and end-systolic dimension at similar
end-systolic pressure indexed systolic function.
End-diastolic pressure (EDP), time constant of relaxation
(tau, assuming a nonzero decay asymptote), and chamber
stiffness (ß) from a monoexponential fit to the
diastolic pressure-dimension curve22 indexed
diastole.
Histological Analysis
Formalin-fixed endocardial biopsies were embedded in paraffin,
and 5-µm serial sections were stained with hematoxylin-eosin and the
collagen-specific stain picrosirius red F3BA (PSR).
Histological examination was performed blinded to
protocol as described in Henegar et al17 at a total
magnification of x400. Myocyte necrosis and PSR staining for collagen
content were graded qualitatively by an individual blinded to the
conditions underlying the biopsy.
In Vitro and In Situ Zymography
MMP abundance was assessed by in vitro gelatin zymography as
previously described.22 Ten to 40 µg total protein was
loaded onto 10% polyacrylamide gels containing 0.1% gelatin
(Novex Chemical), and after electrophoresis, gels were stained with
0.5% Coomassie blue R250. Metalloproteinases produced gelatin lysis
(semiquantified by reverse-image densitometry), and zymogen activation
was suggested by doublet band formation.
In vivo MMP activation is often accompanied by coexpression of tissue inhibitors of metalloproteinases (TIMPs), and this interaction is lost with in vitro zymography, limiting its use for determining net activity. We therefore also performed in situ zymography by incubating fresh-frozen 4-µm slices with 0.1 mg/mL gelatin–oregon green (Molecular Probes) in 1x developing buffer (see online supplementary information, http://www.circresaha.org). Gelatin lysis was visualized by fluorescence microscopy. Coincubation with 50 mmol/L EDTA or MMP-9 antibody confirmed MMP and MMP-9 activity, respectively.
Statistical Analysis
Data are presented as mean±SEM. Within-group
comparisons were made by paired t test. Between-group
analysis was performed by ANOVA with a post hoc Tukey test.
Histopathology scores were assessed by Kruskal-Wallis test.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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Baseline Data and Dose-Dependent Effects of Chronic ß-Adrenergic Blockade
Baseline hemodynamic parameters were very similar among the 5 study groups (Table 1
). To assess the efficacy of
ß-receptor blockade, the inotropic response to isoproterenol was
evaluated in each dog. In low-dose atenolol–treated animals, there was
a 41% decline in maximal isoproterenol (0.80±0.09 µg
· kg-1 · min-1
IV) inotropic response, assessed by a dP/dtmax
normalized to EDD (to adjust for preload change) (Figure 1). Inotropic stimulation was nearly
totally blocked in animals receiving the higher dose. Figure 1
also shows that baseline dP/dtmax/EDD rose
modestly after 1 week of low-dose atenolol and declined to a similar
extent in high-dose–treated animals (both P<0.05). The
latter was accompanied by a -23±4.8% decline in basal HR.
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P<0.05
vs pre–ß-blocker control.
Synergy Between Ang II and 48hP
Figure 2A displays example
pressure-dimension relations for animals exposed to Ang II combined
with 48hP. This interaction resulted in systolic depression
similar to that induced by 48hP alone but markedly increased
diastolic stiffening (elevated chamber stiffness [ß]
and EDP) that was not observed with either 48hP or Ang II
alone.22 Table 2 summarizes
these results, listing absolute changes in cardiac systolic and
diastolic parameters versus baseline for the
Ang II+48hP, 48hP-only, and Ang II–only groups. Heart rate was not
significantly altered in any of these groups.
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Influence of ß-Adrenergic Blockade on Ang II–48hP
Effects
Figure 2B
displays pressure-dimension data for
representative animals treated concomitantly with
atenolol. Regardless of dose, atenolol treatment had no significant
effect on systolic cardiodepression associated with subsequent
Ang II+48hP; however, high-dose ß-blockade (group 2B) prevented the
synergistic exacerbation of diastolic stiffening. In
contrast, there was no inhibitory effect from partial
blockade (low-dose atenolol). Neither dose altered the delay of
pressure relaxation (tau) induced by 48hP, suggesting that the
ameliorative effect of high-dose atenolol was targeted to passive
diastolic properties.
In Vitro Zymography
Figure 3 shows gelatin zymograms
from atenolol-treated animals. Baseline tissue (B) displayed minimal
gelatin lysis, indicating low levels of MMP expression and activation
in normal canine hearts. The upper gel shows typical changes after 1
week of low- or high-dose atenolol before and after the addition of 4
days of Ang II infusion. Gelatin lysis in the regions comigrating with
human MMP-9 (indicated by positive controls) was consistently
observed in each ß-blocker+Ang II lane and appeared as a doublet,
consistent with zymogen activation (lower-molecular-weight
activated enzyme). This was not present in control or
ß-blocker-only–treated tissue (P<0.01 for both dose
groups, total n=21). In separate analysis, we compared gel
lysis with ß-blocker+Ang II to that with Ang II
only22 and found no significant change with
ß-blockade.
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In contrast to the results with Ang II alone, high-dose atenolol had a
marked inhibitory effect on gelatin lysis (Figure 3, bottom) once 48hP was superimposed. Lysis declined to near control
levels in high-dose-atenolol–treated hearts (3 right lanes). In
contrast, hearts treated with low-dose atenolol revealed persistent
lysis in the MMP-9 region and in some instances, in the region in which
human MMP-2 migrated (also identified in positive control lane),
similar to that observed without ß-blockade22
(P=0.03 versus high-dose, n=7 in each group).
In Situ Zymography
Figure 4 displays typical results of
in situ zymography. Control tissue (Figure 4a) displayed minimal
gelatin digestion, resulting in a uniform dark background with
blue-stained nuclei. In contrast, Ang II+48hP tissue (Figure 4b)
showed substantial digestion, evidenced by the appearance of green
fluorescence. Positive staining was blocked by coincubation of
the same tissue with EDTA (Figure 4c), a nonspecific
inhibitor of MMPs, and also was substantially reduced by
coincubation with MMP-9–blocking antibody (Figure 4d). Together
with the in vitro analyses, these data support increased MMP
abundance and tissue activity, and in particular, activity from MMP-9
in this model. Results for hearts exposed to low- or high-dose atenolol
are also shown. High-dose ß-blockade (Figure 4e) inhibited in
situ gelatin lysis, whereas low-dose ß-blockade did not (Figure 4f). Similar results were confirmed in 3 to 4 samples for each
condition. In situ zymography of biopsies exposed to Ang II and
atenolol (ie, before 48hP) were also positive, commensurate with the in
vitro assay (data not shown). Thus, gel lysis observed by in vitro
zymography correlated with MMP activity in tissues examined by in situ
assay.
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Collagen Staining and Cellular Histology
Both Ang II alone and Ang II+48hP induced myocardial tissue
damage, characterized by patchy myocyte necrosis with neutrophil and/or
fibroblast infiltration,22 similar to that reported in rat
hearts.17 This damage was significantly inhibited by
high-dose but not low-dose ß-blockade. Figure 5A displays tissue from a low-dose group
after 4 days of Ang II exposure, revealing necrotic damage (arrow) and
corresponding fibrosis (Figure 5B). Myocardial damage persisted with
superimposition of tachypacing (P=0.02, data not shown);
however, collagen staining consistently declined (Figure 5C).
This is intriguing, given that diastolic stiffening was
observed principally during this period. Figure 5D through 5F
displays analogous data from a heart treated with high-dose atenolol.
There was generally less myocardial damage with Ang II and Ang II+48hP
(Figure 5D) and less fibrosis. Summary histology and collagen scores
are provided in Figure 5G. Fibrosis was greatest in group 2A,
exposed to Ang II before the onset of tachypacing (and
diastolic stiffening), with less collagen observed in both
low- and high-dose-atenolol–treated tissue after superimposition of
48hP.
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Discussion |
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Adverse consequences from adrenergic and renin-angiotensin stimulation in heart failure are well recognized, yet the mechanisms for this interaction and cross-talk between the systems remain less well understood. The present study provides novel information in this regard. We found that marked exacerbation of diastolic dysfunction induced by combining Ang II infusion with 48hP was prevented by ß-receptor blockade. This normalization of chamber stiffness was accompanied by inhibition of myocardial MMP abundance and activation. Use of a blocking antibody to MMP-9 in in situ zymography highlighted this protein in particular, although other MMP species are likely also involved. In contrast, net collagen deposition correlated poorly with diastolic stiffening. These are the first data to confirm MMP activation in situ with Ang II–modulated cardiac dysfunction, and they support a novel link between this change and Ang II–mediated sympathostimulation. These results suggest a novel mechanism by which ß-blockade may limit remodeling and improve function of the failing heart.
Myocardial Effects of Ang II
Elevation of plasma and myocardial Ang II is a common feature of
severe, late-stage cardiac failure. All the necessary enzymes for
generating Ang II exist in the myocardium28
and appear enhanced in heart failure.21 29 Chamber
distension may be important in this regard, because cell stretch can
itself increase the expression of a broad range of
renin-angiotensin system genes in neonatal
myocytes.30 Ang II has potent effects on normal myocytes
that acutely enhance contractile function. These include phospholipase
C–mediated Ca2+ release and myofilament
Ca2+ sensitization10 and
sympathomimetic effects via AT1 receptor binding
to presynaptic nerve terminals.31 The latter enhances NE
release relative to efferent nerve activity and lowers NE reuptake. Ang
II can also modulate the baroreflex and thus trigger
sympathostimulation.16 Sustained Ang II activates
protein kinase C and cellular alkalization, increasing
Ca2+ by
Na+-Ca2+
exchange.11 32
In normal hearts, the net result of acute or 4- to 7-day Ang II exposure is an increase in systolic function, with little to no change in diastolic properties.22 33 However, Ang II induces quite different responses in hearts with established or early-evolving cardiac dysfunction. Cheng et al12 reported that both failing hearts and myocytes exposed to markedly elevated Ang II levels develop systolic depression and worsened diastolic function, in contrast to normal tissues. Furthermore, we recently reported that whereas 1 week of Ang II had negligible effects on diastolic properties of normal hearts, when combined with 48hP, the result was marked synergistic exacerbation of chamber stiffness, with EDPs often exceeding 30 mm Hg.22
The present study demonstrates that sympathostimulation is central in modulating the Ang II–48hP synergy. The ability of high-dose but not low-dose atenolol to inhibit this synergy may have related to incomplete blockade by the latter and/or to loss of ß1 versus ß2 selectivity and thus more comprehensive antagonism with the higher dose.34 35 A key element of this synergy was the superimposition of 48hP. Cardiac failure is associated with reduced efficiency of NE reuptake and increased neuronal release, and both contribute to higher NE drive and gradual depletion of myocardial NE stores.36 37 Under these conditions, AT1 receptor binding might further elevate NE,13 14 15 16 exacerbating catecholamine myotoxicity.38 39 Even 1 day of tachypacing has been shown to influence myocardial adrenergic signaling, reducing high-affinity binding receptors and lowering adenylate cyclase while increasing NE stimulatory drive.40 Although further reduction of adrenergic signaling by more advanced failure might be anticipated to limit sympathotoxicity, we found that near-total ß-blockade was necessary (ie, high-dose atenolol) to inhibit it. Even in severe heart failure, downregulation more compatible with low-dose atenolol data is generally observed.41
Myocardial tissue is induced by Ang II infusion alone in normal rat hearts,17 and this is inhibited by ß-adrenergic blockade.18 However, as shown in this study, this combination did not correlate with systolic or diastolic dysfunction in otherwise normal hearts. However, once 48hP was instituted, persistence of these changes in the low-dose group did correlate with worsened diastolic dysfunction. This probably reflects additional sympathetic-mediated myotoxicity.
Effects of Ang II on the Interstitium
In addition to myocyte effects, Ang II has potent influences on
the cardiac interstitium mediated principally via the
AT1 receptor on fibroblasts.19 Ang
II stimulates fibroblasts in culture to increase types I and III
collagen synthesis and reduce MMP1 (interstitial
collagenase) activity.19 21
AT2-receptor binding may inhibit this cascade,
because Ang II–mediated collagen synthesis nearly doubles in the
presence of AT2-receptor blockade.20
The present data also revealed Ang II–mediated fibrosis, primarily
in the low-dose atenolol group, and similar to data in nontreated
animals,22 but this was not observed when chamber
stiffening was most marked. Rather, collagen deposition declined with
superimposition of 48hP despite chamber stiffening. This suggests that
changes in the tertiary structure42 and/or extracellular
environment (ie, collagen turnover, MMP activation) may be more
important than absolute collagen content.
Only a few recent studies have examined the role of MMPs in cardiac failure, and little is currently known about the mechanisms or physiological consequences of their activation. Elevated MMP expression in human failure was reported by Gunja-Smith et al,43 who found increases in association with reduced TIMP-1, and by Thomas et al,25 who reported marked increases in MMP-3 and MMP-9 with increases in TIMP-1. Experimental models of failure, including the tachypacing model,23 24 have also reported increased MMP abundance by zymography and immunoblot. Such MMP activation may play a role in cardiac remodeling, as recently suggested by the ability of an MMP inhibitor to limit murine infarct dilation.44
MMPs are normally present in the extracellular matrix in an inactive form, resulting from noncovalent interactions between coordinated Zn2+ at the active site and Cys in the prodomain. In vivo activation occurs via a broad range of serine proteases, cytokines, and reactive oxygen species.45 46 In cardiac tissue, we have consistently observed minimal MMP synthesis by in vitro zymography under baseline conditions, and the present study extends this to tissue activity by in situ assay. However, exposure to only 4 days of Ang II infusion results in marked increases in both MMP abundance and activity. The in situ zymography identified a role for MMP-9, and Ang II could mediate its expression via linkage to the AP-1 transcription factor.47 48 49 Generation of reactive oxygen species by Ang II and sympathostimulatory toxicity and inflammation could contribute to its activation.46 49 50 51 In this regard, it is worth noting that MMP activation was also observed with Ang II+high-dose atenolol, despite minimal tissue damage or inflammation, indicating that alternative pathways also existed.
MMP activation had minimal impact by itself on global chamber function. However, the persistence of activity during Ang II+48hP was associated with diastolic stiffening.22 The present data are consistent with a linkage between these behaviors, in that high-dose atenolol substantially inhibited both. Ang II also enhances coronary vascular permeability associated with increased gelatinase52 and thus could potentially contribute to myocardial edema. Only small increases of interstitial water content can greatly increase chamber stiffness.53 54 Furthermore, MMPs can degrade proteoglycans and mucopolysaccharides (such as hyaluronidate), molecules that become highly hydrophilic when structurally uncoiled.55 56 This could serve as an interstitial sponge contributing to water retention and diastolic stiffening. Altered collagen cross-linking might also play a role.42 Sustained MMP activation during 48hP might therefore influence diastolic properties by providing an abnormal extracellular environment with which the myocytes interact, and as myocyte function declined, this could play a greater role.
Experimental Limitations
Given the complex chronic preparation involved in these studies,
we did not perform catecholamine spillover studies with
radiolabeled tracers and coronary sinus and
arterial blood sampling. One would predict a substantial
rise in spillover associated with Ang II, and even more so with Ang
II superimposed with cardiac depression from pacing. As noted earlier,
heart failure and Ang II both enhance NE release and diminish neuronal
uptake,13 14 15 36 37 so their interaction may be
particularly potent.
In vitro zymography was useful for identifying the presence of MMPs but was not ideal for determining their activation or the precise species involved. Although immunoblotting can resolve the latter issue, we instead performed in situ zymography to identify particular species (ie, MMP-9) with blocking antibody and to yield key information regarding tissue activation. However, some other MMPs, such as membrane-bound species, and extracellular matrix inducer protein57 might be upregulated in this model, and these changes would not be assayed by either approach. Clarifications of these issues await further study.
Conclusions
In conclusion, we have shown that synergistic antagonism of
diastolic chamber dysfunction and activation of myocardial
MMPs from Ang II combined with evolving cardiac depression are due to
sympathostimulation. The data further suggest a novel mechanism by
which ß-blockade may limit chamber remodeling and improve
diastolic dysfunction by offsetting Ang II–mediated
toxicity.
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Acknowledgments |
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This study was supported by grants from the National Institutes of Health, P50–52307 (D.A.K.), 1-T32-HL-781603, and PO1-HL-42550 (M.L.L.); an American Heart Association (Maryland Affiliate) Fellowship Grant; a University of Tokyo Fellowship Grant (H.S.); and a Fellowship Award from Università degli Studi di Perugia (N.P.). The authors thank Richard Tunin for his excellent surgical expertise and assistance in performing these protocols.
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Footnotes |
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This manuscript was sent to Richard A. Walsh, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received September 20, 1999; accepted January 5, 2000.
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